New Insights into Biliverdin Reductase Functions: Linking Heme Metabolism to Cell Signaling

摘要

Biliverdin reductase (BVR) functions in cell signaling through three distinct tracks: a dual-specificity kinase that functions in the insulin receptor/MAPK pathways (25, 29, 51); a bzip-type transcription factor for ATF-2/CREB and HO-1 regulation (1,25); and a reductase that catalyzes the conversion of biliverdin to bilirubin (27). These, together with the protein's primary and secondary features, intimately link BVR to the entire spectrum of cell-signaling cascades. Nearly four decades ago, an NADH-dependent enzyme that converts biliverdin to bilirubin was described (55). Later this enzyme was defined as an NADPH-dependent reductase (58). A decade later, the enzyme, known as "biliverdin reductase" (BVR) was obtained in homogeneous form and its unique dual pH/cofactor activity profile was revealed (27). The reductase activity is NADH dependent at acidic pH, whereas NADPH is used in the basic range. Searching for the molecular basis for this feature of BVR has recently culminated in unraveling other fascinating secrets of a protein with an uncanny spectrum of potential functions in cell-signaling pathways. Those functions, together with its unique structural features, underscore the central role of this unusual protein in cell signaling.